Systems and methods for freezing, storing and thawing biopharmaceutical materials

ABSTRACT

A system for using freezing, storing and thawing biopharmaceutical materials which includes a holder and a container for holding biopharmaceutical materials therein. The holder has a cavity and the container is received in the cavity. The holder includes a first portion and second portion. The container is received between the first portion and the second portion to connect the container to the holder. The holder includes an interior cradle having a bottom and edges extending from the bottom. The cradle bounds the cavity. An outer rim is connected to the cradle and separated from the cavity. The bottom includes an inner surface facing the cavity receiving the container and an outer surface. The outer surface of the bottom is recessed relative to an outer surface of the outer rim.

TECHNICAL FIELD

This invention relates, in general, to biopharmaceutical materials,preservation methods and systems, and more particularly to systems andmethods for freezing, storing and thawing biopharmaceutical materials.

BACKGROUND ART

Preservation of biopharmaceutical materials, such as cryopreservation,is important in the manufacture, use, transport, storage and sale ofsuch materials. For example, biopharmaceutical materials are oftenpreserved by freezing between processing steps and during storage.Similarly, biopharmaceutical materials are often frozen and thawed aspart of the development process to enhance the quality or to simplifythe development process.

When freezing biopharmaceutical materials, the overall quality, and inparticular pharmaceutical activity, of the biopharmaceutical materialsis desirably preserved, without substantial degradation of thebiopharmaceutical materials.

The preservation of biopharmaceutical material, particularly in bulkquantities, often involves placing a container containing liquidbiopharmaceutical material in a cabinet freezer, chest freezer orwalk-in freezer and allowing the biopharmaceutical material to freeze.Specifically, the container, which is typically one or more liters involume and may range up to ten or more liters, is often placed on ashelf in the cabinet freezer, chest freezer or walk-in freezer and thebiopharmaceutical material is allowed to freeze. These containers may bestainless-steel vessels, plastic bottles or carboys, or plastic bags.They are typically filled with a specified volume to allow for freezingand expansion and then transferred into the freezers at temperaturestypically ranging from negative 20 degrees Celsius to negative 70degrees Celsius or below.

Disposable bulk storage containers such as plastic bags or otherflexible containers often are damaged, leading to loss of thebiopharmaceutical material. Particularly, the volumetric expansion ofthe biopharmaceutical materials during freezing could generate excessivepressure in an over filled bag or in a pocket of occluded liquidadjoining the bag material, possibly leading to rupture or damage to theintegrity of the bag. Moreover, handling of such disposable containers,such as plastic bags, during freezing, thawing, or transportation ofthese containers often result in damage thereof, due, for example, toshock, abrasion, impact, or other mishandling events arising fromoperator errors or inadequate protection of the bags in use.

Similarly, thawing of bulk biopharmaceutical materials may involveremoving them from a freezer and allowing them to thaw at roomtemperature. In certain situations thawing can also lead to productloss. In addition, in certain situations rapid thawing ofbiopharmaceutical materials may result in less product loss than slowerthawing. Further, it may also be desirable to control temperature of thebiopharmaceutical materials during a thawing process since exposure ofsome biopharmaceutical materials to elevated temperatures in certainsituations may also lead to product loss. For example, it may bedesirable to maintain a thawing biopharmaceutical material at about 0°C. when still in liquid and solid form during thawing thereof. Insituations where thawing is desirable it is necessary to protect thebiopharmaceutical material from damage which may occur due to impact orrupture to the containers.

Thus, there is a need for systems and methods for freezing, thawing, andstoring biopharmaceutical materials, including in bulk quantities, thatdo not result in loss of biopharmaceutical material, and are repeatable.In addition, there is a need for containers usable for the freezing,thawing and storing of biopharmaceutical materials, including in bulkquantities, which allow the freezing, thawing and transporting ofbiopharmaceutical materials therein without damage thereto, and whichallow for the storage thereof to occur in an organized manner whileprotecting the biopharmaceutical material.

SUMMARY OF THE INVENTION

The present invention provides, in a first aspect, a system for use infreezing, storing and thawing biopharmaceutical materials which includesa holder and a container for holding biopharmaceutical materialstherein. The holder has a cavity and the container is received in thecavity. The holder includes a first portion and second portion. Thecontainer is received between the first portion and the second portionto connect the container to the holder. The holder includes an interiorcradle having a bottom and edges curving upwardly from the bottom. Thecradle bounds the cavity. An outer rim is connected to the cradle andseparated from the cavity. The bottom includes an inner surface facingthe cavity receiving the container and an outer surface. The outersurface is recessed relative to an outer surface of the outer rim.

The present invention provides, in a second aspect, a system for use infreezing, storing and thawing biopharmaceutical materials which includesa container for holding biopharmaceutical materials therein. A holderhas a cradle bounding a cavity and the container is received in thecavity. The holder includes a first portion and a second portion formingthe cradle and the container is received between the first portion andthe second portion to connect the container to the cradle. A supportmember protrudes from an outer surface of the cradle. The support memberstructurally supports the cradle and inhibits the deformation of thecradle in response to an expansion of biopharmaceutical material held inthe container due to freezing.

The present invention provides, in a third aspect, a system for use infreezing, storing and thawing biopharmaceutical materials which includesa container for holding biopharmaceutical materials therein. A holderhas a cradle bounding a cavity and the container is received in thecavity. The holder includes a first portion and a second portion formingthe cradle and the container is received between the first portion andthe second portion to connect the container to the holder. The holderincludes an outer rim connected to the cradle. The outer rim includes afirst plurality of outer teeth engageable with a second plurality ofouter teeth of a second outer rim of a second holder to stack the holderand the second holder and to inhibit movement between the holder and thesecond holder.

The present invention provides, in a fourth aspect, a method for use infreezing, storing and thawing biopharmaceutical materials which includesproviding a holder having a cavity and the holder having a first portionand a second portion. The holder has an interior cradle having a bottomand edges curving upwardly from the bottom. The cradle portion boundsthe cavity. The holder has an outer rim connected to the cradle andseparated from the cavity. The bottom includes an inner surface facingthe cavity and an outer surface. The outer surface of the bottom isrecessed relative to an outer surface of the outer rim. A container forholding biopharmaceutical materials is received in the cavity of theholder and between the first portion and the second portion to connectthe container to the holder.

The present invention provides, in a fifth aspect, a method for use infreezing, storing and thawing biopharmaceutical materials which includesproviding a holder having a first portion and a second portion forming acradle bounding a cavity. A container for holding biopharmaceuticalmaterials is received in the cavity of the holder and between the firstportion and the second portion to connect the container to the holder. Asupport member protrudes from an outer surface of the cradle. Thesupport member structurally supports the cradle and inhibits deformationof the cradle in response to an expansion of biopharmaceutical materialsheld in the container due to freezing.

The present invention provides, in a sixth aspect, a method for use infreezing, storing and thawing biopharmaceutical materials which includesconnecting a container for holding biopharmaceutical materials to aholder by receiving the container in a cavity of a cradle of the holder.The cradle is formed by a first portion and a second portion of theholder. A first plurality of outer teeth of an outer rim of the holderis engaged with a second plurality of outer teeth of a second outer rimof a second holder to stack the holder and the second holder and toinhibit movement between the holder and the second holder.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter which is regarded as the invention is particularlypointed out and distinctly claimed in the claims at the conclusion ofthe specification. The foregoing and other features, and advantages ofthe invention will be readily understood from the following detaileddescription of preferred embodiments taken in conjunction with theaccompanying drawings in which:

FIG. 1 is a perspective view of a holder receiving a container inaccordance with the present invention;

FIG. 2 is a perspective view of a first portion and second portion ofthe holder of FIG. 1;

FIG. 3 is a top elevational view of a container receivable in the holderof FIG. 1;

FIG. 4 is a perspective view of a portion of the holder of FIG. 1receiving the container of FIG. 3;

FIG. 5 is a side elevational view of the holder of FIG. 1 stacked on asecond holder in accordance with the present invention;

FIG. 6 is a side cross-sectional view of a portion of FIG. 2 showing aportion of a bottom portion of the holder receiving the container ofFIG. 3 in simplified form;

FIG. 7 is a cross-sectional view of another holder in accordance withthe present invention and showing opposite bottom portions curvingtoward each other;

FIG. 8 is a side-elevational view of another holder in accordance withthe present invention showing the first portion of a first holderstacked on the second portion of a second holder

FIG. 9 is a perspective view of a top portion of another holder inaccordance with the present invention;

FIG. 10 is a perspective view of a bottom portion of the holder of FIG.9;

FIG. 11 is a perspective view of a top portion of a further holder inaccordance with the present invention;

FIG. 12 is a perspective view of a bottom portion of the holder of FIG.11;

FIG. 13 is a side cross-sectional view in simplified form of a portionof another holder in accordance with the present invention, receivingthe container of FIG. 3

FIG. 14 is a side cross-sectional view of the holder of FIG. 13 insimplified form showing top and bottom portions thereof explodedrelative to a protective member thereof; and

FIG. 15 is a side cross-sectional view in simplified form of the top andbottom portions of FIG. 14 connected to the protected member thereof.

DETAILED DESCRIPTION

In accordance with the principles of the present invention, systems andmethods for freezing, thawing and storing biopharmaceutical materialsare provided.

In an exemplary embodiment depicted in FIGS. 1-6, a system 5 forcooling, freezing, preserving, processing and thawing biopharmaceuticalmaterials is shown. The system may include a sterile container, such asa flexible container 10, configured to contain the biopharmaceuticalmaterials and configured to be supported by a supporting and/orprotective structure, such as a holder 15.

Flexible container 10 may be formed of a laminated film which includes aplurality of layers and may have an interior volume ranging from0.01-100 liters, (e.g., 0.1-20 L) as depicted in FIGS. 3-4 for example.Further, flexible container 10 could be available in a variety of sizesto accommodate different uses, for example, 5-10 liter flexiblecontainers, such as 8-liter containers, may be utilized. Also abiocompatible product-contacting layer of the interior of flexiblecontainer 10 may be formed of a low density polyethylene, very lowdensity polyethylene, ethylene vinyl acetate copolymer, polyester,polyamide, polyvinylchloride, polypropylene, polyfluoroethylene,polyvinylidenefluoride, polyurethane or fluoroethylenepropylene, forexample. A gas and water vapor barrier layer may also be formed of anethylene/vinyl alcohol copolymer mixture within a polyamide or anethylene vinyl acetate copolymer. Further, flexible container 10 mayinclude a layer with high mechanical strength (e.g. a polyamide), and anexternal layer with insulating effect to heat welding, for example,polyester. The layers may be compatible with warm and cold conditionsand may be able to withstand ionizing and gamma irradiation forsterilization purposes. Also, flexible container 10 may have a largesurface area to volume ratio, and a relatively thin wall thus promotingheat transfer therethrough when received in a temperature control unitsuch as an interior 500 of a walk-in or blast freezer (FIG. 1). Oneexample of materials useful for formulation of flexible container 10 isdescribed in U.S. Pat. No. 5,988,422 to Vallot, the entire subjectmatter of which is hereby incorporated herein by reference.

Container 10 may be adapted to receive and contain frozen and/or liquidbiopharmaceutical materials. In an embodiment, the biopharmaceuticalmaterials may comprise protein solutions, protein formulations, aminoacid solutions, amino acid formulations, peptide solutions, peptideformulations, DNA solutions, DNA formulations, RNA solutions, RNAformulations, nucleic acid solutions, nucleic acid formulations,antibodies and their fragments, enzymes and their fragments, vaccines,viruses and their fragments, biological cell suspensions, biologicalcell fragment suspensions (including cell organelles, nuclei, inclusionbodies, membrane proteins, and/or membranes), tissue fragmentssuspensions, cell aggregates suspensions, biological tissues insolution, organs in solution, embryos in solution, cell growth media,serum, biologicals, blood products, preservation solutions, fermentationbroths, and cell culture fluids with and without cells, mixtures of theabove and biocatalysts and their fragments.

Container 10 may be configured (e.g., shaped and dimensioned) to bereceived in, and connected to holder 15 (FIGS. 1-2 and 4-5), which actsas a protector, supporting structure or frame for supporting flexiblecontainer 10. In one example, container 10 may have a pillow-shape.Holder 15 may be configured to protect a container held therein duringfilling, transport, storage, and/or freezing of biopharmaceuticalmaterials. For example, holder 15 may hold and protect container 10during freezing of biopharmaceutical materials in interior 500 of awalk-in or blast freezer (FIG. 1). Further, holder 15 may protectcontainer 10 when holder 15 is stacked on or under another holder (e.g.,holder 515, (FIG. 5)) similar to holder 15.

For example, holder 15 may include a first portion 115 and a secondportion 117 forming a cradle 202 having a cavity 240 when connected toone another. First portion 115 has a bottom 200 and upwardly curvingsides 210. Second portion 117 has a bottom 220 and upwardly curvingsides 230. Bottom 200, upwardly curving sides 210, bottom 220 andupwardly curving sides 230 form cradle 202 which bounds cavity 240.Container 10 may be received in cavity 240 and may be connected to firstportion 115 and/or second portion 117. For example, container 10 may beheat sealed or otherwise connected to first portion 115 and/or secondportion 117 to prevent or inhibit separation of container 10 therefrom.

An inner rim 30 of first portion 115 may be connected to an outer rim 40of first portion 115 as depicted in FIG. 2. Inner rim 30 may include asubstantially flat holding or clamping portion 50 and a connectingportion 60, both of which may extend partially or entirely around aninner circumference of holder 15. Similarly, an inner rim 70 of secondportion 117 may be connected to an outer rim 80. Inner rim 70 mayinclude a substantially flat holding or clamping portion 90 and aconnecting portion 95, both of which may extend partially or entirelyaround an inner circumference of holder 15. Holding or clamping portion50 and holding or clamping portion 90 may be configured to hold or clampcontainer 10 therebetween before it is filled with biopharmaceuticalmaterials to center the container in the cradle and cavity 240. Forexample, holding portion 50 and holding portion 90 may be spaced fromeach other to provide a particular amount of friction to container 10such that as container 10 is filled with the biopharmaceuticalmaterials, an edge or portion of the container may move from a positionbetween the holding portions, or external to the holding portions intocavity 240. Thus, as container 10 is filled with biopharmaceuticalmaterials, container 10 may expand in cradle 202 to conform to the innersurfaces (i.e., bottom 200, upwardly curving sides 210, bottom 220 andupwardly curving sides 230) of cradle 202 bounding cavity 240. Also,container 10 may include an external flange 11 on opposite edges thereofconfigured to be received between holding or clamping portion 50 andholding or clamping portion 90 to hold the container in the cradlethereof. Such flange may be attached, or may be monolithic relative to,an outer circumference of the container and may be formed of the samematerial thereof.

A protective cavity 45 of holder 15 may be bounded by outer rim 40 whichis connected to inner rim 30 as depicted in FIGS. 2 and 6. Also, aprotective cavity 85 of second portion 117 may be bounded by outer rim80 which is connected to inner rim 70. Protective cavity 45 andprotective cavity 85 may extend circumferentially around holder 15.Outer rim 40 may include an inner wall 32 adjacent inner rim 30, abottom surface 33 (corresponding to an opposite side of teeth 450) andan outer wall 34. Outer rim 80 may include an inner wall 72 adjacentinner rim 70, a bottom surface 73 and an outer wall 74. The protectivecavities (i.e., cavity 45 and cavity 85) allow holder 15 to receivestresses, impacts, or shocks to an outer wall 17 of holder 15 whileinhibiting or preventing damage to container 10 held in cavity 240. Forexample, an impact to outer wall 17 may cause outer wall 17 totemporarily move towards the inner rims into the protective cavitiessuch that the outer walls of the outer rims absorb or dampen the shockand damage to the container is inhibited. Outer wall 17 may includeouter wall 34 forming an exterior surface of outer rim 40 of firstportion 115 and outer wall 74 forming an exterior surface of outer rim80 of second portion 117. Outer wall 17 may be formed of an elasticallydeformable or resilient materials such as PET or HDPE. Further, each offirst portion 115 and second portion 117 may be formed monolithically orthey may be formed of separate elements connected together. Also,protective cavities 45 and 85 may provides storage for conduitsincluding tubing, connectors and clamps therefor.

First portion 115 and second portion 117 may be connected together viaengagement of connecting portion 95 and connecting portion 60. Forexample, each of connecting portion 60 and connecting portion 95 mayinclude multiple teeth 350 extending upwardly away from bottom 200 andbottom 220, respectively. The teeth on connecting portion 95 andconnecting portion 60 may alternate such that they may be inserted intothe spaces between opposing teeth to connect (e.g., via interlocking theteeth) first portion 115 to second portion 117. The teeth may alternatecontinuously around perimeters of connecting portion 95 and connectingportion 60 or clusters of the teeth (e.g., teeth 350) may beintermittent around the perimeters thereof. The interlocking of theteeth of connecting portion 95 and connecting portion 60 may alsosupport a sheer load during an impact or drop to avoid a sheer loadbeing applied to the fasteners or welds connecting first portion 115 andsecond portion 117 to one another. Container 10 may include openings 12(e.g., at or near outer edges thereof) to allow teeth to passtherethrough to connect container 10 to holder 15 and to inhibitmovement of container 10 relative to holder 15 when the teeth areengaged and clamping portion 50 and connecting surface 90 abut container10. In one example, the spacing of the teeth or groups of teethintermittently may allow the connecting portions and/or holding portions(e.g., holding portion 50 and holding portion 90) to hold (e.g., inhibitmovement of) the container in the portions of the inner rims between theteeth. In another example, a flange (e.g., flange 11) may be receivedbetween connecting portion 95 and connecting portion 60 without teeth350 thereof passing through the openings (e.g., openings 12) in thecontainer (e.g., container 10).

Bottom 200 and bottom 220 may include a plurality of first openings 201and a plurality of second openings 221, which may allow heat transferfrom an exterior of holder 15 to biopharmaceutical materials held incontainer 10 in cavity 240 of holder 15. Any number of apertures and anydesign or placement of the apertures relative to one another on thebottoms may be provided to facilitate such heat transfer while stillallowing the bottoms to provide structure/support to a container incradle 202. Further, the openings may be placed relative to one anotherand the container may be formed of material such that the containerremains offset from the openings (i.e., toward an interior of thecradle) when the biopharmaceutical materials held therein are in aliquid form. The offset of the container's surface from the openingsinhibits any potential damage to the container from external hazardswhich may come near bottom 200 or bottom 220.

Also, bottom 200, bottom 220, sides 210 and sides 230 of cradle 202 maybe connected to outer rim 40 by one or more support members or supportribs 300 providing structural support as depicted in FIG. 1, forexample. Such ribs may extend across bottom 200 to connect bottom 200and opposite sides of outer rim 40 to one another. Also, the ribs mayextend across bottom 220 to connect opposite sides of outer rim 80 toone another and to bottom 220. Alternatively, one or more of ribs 300may extend from outer rim 40 to bottom 200 or sides 210 withoutextending from one side of outer rim 40 to another side thereof. Ribs300 may be raised relative to an exterior surface 205 of bottom 200 asdepicted in FIG. 1. An interior side 206 of bottom 200 may also includegrooves 208 (FIG. 2) which correspond to ribs 300 on exterior surface205 of bottom 200. Similarly, ribs 300 may be connected to bottom 220and sides 230 and/or to opposite sides of outer rim 80 to providestructural support to cradle 202. Also, ribs 300 may be raised relativeto an exterior surface (not shown) of bottom 220 while an interiorsurface 223 may have grooves 224. The connection of support ribs (e.g.,ribs 300) to cradle 202 structurally supports the cradle and inhibitsdeformation of a shape of the cradle in response to expansion ofbiopharmaceutical materials held in container 10 due to freezing. Inanother example, holder 15 may not have ribs 300 and instead may bereinforced by rods or cushioned by pads formed of textiles, foam, orother resilient materials.

As indicated above, the container (e.g., container 10) may avoidextending into openings 201 and 221 when biopharmaceutical materialsheld in the container are in a liquid form. Further, the container mayalso avoid extending into grooves 208 when such biopharmaceuticalmaterials are in a liquid form. Upon the biopharmaceutical materialsundergoing a freezing: process, the container and biopharmaceuticalmaterials held therein may extend into grooves 208, openings 201, andopenings 221. The movement of freezing biopharmaceutical materials intogrooves 208, openings 201, and openings 221 provide locations forexpansion of the biopharmaceutical materials thereby allowing for lessexpansion of bottom 200 and bottom 220 in directions away from oneanother than would otherwise be the case absent the movement ofbiopharmaceutical materials into these locations.

Further, a space 600 may extend between exterior surface 205 of bottom200 and an exterior surface 207 of inner wall 32 of outer rim 40 asdepicted in FIGS. 1 and 6. Space 600 may also be bounded by an exteriorsurface 215 of upwardly extending sides 210 and a bottom 610 of space600, which may be an exterior surface corresponding clamping portion 50and connecting surface 90 on the opposite of holder 15. As describedabove relative to protective cavity 45 and protective cavity 85, thespace between outer rim 40 and exterior surface 205 of bottom 200 mayprovide protection to container 10 held in cradle 202. In particular, animpact, shock or stress to outer rim 40 may cause outer rim 40 (e.g.,exterior surface 207) to move into, or deform (e.g., elastically orresiliently) toward space 600 thereby absorbing the impact, shock orstress and inhibiting the impact, shock or stress from being applied tocontainer 10 and the biopharmaceutical materials held therein.Similarly, a space (not shown) may be provided between an exteriorsurface (not shown) of bottom 220 and outer rim 80 to inhibit damage tocontainer 10 and biopharmaceutical materials held therein.

Outer rim 40 may have a height different than exterior surface 205 ofbottom 200 and ribs 300 thereon such that outer rim 40 is raisedrelative to exterior surface 205 and ribs 300 as depicted in FIG. 1. Thedifference in height between the outer rim and the exterior surface ofthe bottom of the holder allows expansion of biopharmaceutical materialsheld in container 10 in cradle 202 due to freezing while avoiding theexterior side (i.e., exterior surface 205) extending beyond outer rim40. Similarly, outer rim 80 may have a height different than theexterior surface (not shown) of bottom 220 and ribs 300 thereon suchthat outer rim 80 is raised relative to the exterior surface and ribs300 thereby allowing expansion of biopharmaceutical materials held incontainer 10 in cradle 202 due to freezing while avoiding the exteriorside of bottom 220 from extending beyond outer rim 80.

Further, water and aqueous solutions expand by about ten percent whenfrozen and such expansion may be non-uniform. In one example, whencontainer 10 is received in cradle 202 the container may be filled withbiopharmaceuticals such that cradle 202 may accommodate the expansiondue to freezing of the biopharmaceutical materials, i.e., the cradle isnot filled with biopharmaceutical materials to its volumetric capacityin a liquid state and instead space exists to allow expansion of thebiopharmaceutical materials within cradle 202. Also, in another examplebottoms 200 and 220 of cradle 202 may curve inwardly toward one another(i.e., the shape thereof may be concave when viewed from an exterior ofcradle 212 as depicted in FIG. 7) before freezing of biopharmaceuticalmaterials and the expansion of the biopharmaceutical materials may causethe bottoms to move apart from each other such that they aresubstantially flat on outer surfaces (e.g., exterior surface 205)thereof.

Further, the difference in height between each of the outer rims and theexterior surfaces of the bottoms of the holder (i.e., even afterfreezing of the biopharmaceutical materials) inhibits damage to thebiopharmaceutical materials held in container 10, along with container10 itself. In particular, the bottoms (e.g., bottoms 200 and 220) of theholder may not contact any objects adjacent to holder 15 or abuttingholder 15 resulting from such objects instead contacting the outerrim(s), as depicted in FIG. 5. For example, when holder 15 lieshorizontally on a surface 502 of an interior (e.g., an interior 502) ofa blast freezer, outer rim 80 may contact the surface and outer rim 40may contact an object (e.g., a holder 515) stacked on top of holder 15,but neither bottom 200 nor bottom 220 may contact the surface or theobject due to the space between the exterior surface (e.g., exteriorsurface 205) of the bottoms and any object resulting from the differencein height between the outer rims and the exterior surfaces of thebottoms.

The outer rims (e.g., outer rim 40 and outer rim 80) may also have teeth450 (FIG. 1) to allow holder 15 to be connected (i.e., by interlockingthe teeth) to a second similar holder, such as holder 515, havingcomplementary teeth on an outer rim thereof as depicted in FIG. 5. Thedifference in height between the outer rims and exterior surfaces alsoallows the stacking of multiple holders (e.g., holder 15 and holder 515)on the outer rims thereof and the engagement of the corresponding teethin contrast to stacking the exterior surfaces (e.g., exterior surface205) on each other. For example, the difference in heights between theouter rims and exterior surfaces is advantageous particularly when suchexterior surfaces (e.g., exterior surface 205) may be deformed (e.g., bya mounding effect) due to the expansion of freezing biopharmaceuticalmaterials held in containers therein thereby making stacking difficult.In this case, the stacking of the holders on the outer rims minimizesany interference that may be caused by deformation of the exteriorsurfaces. More particularly, the height difference between the rims andthe exterior surfaces allow the expansion of the biopharmaceuticalmaterials held in container 10 in cradle 202 toward an outer surface ofthe outer rim (e.g., outer rims 40 and 80) while avoiding the exteriorsurfaces from extending beyond the outer surfaces of the outer rims. Theexpansion of the exterior surface beyond the outer rims may otherwise(i.e., absent the raised height of the rims relative to the exteriorsurfaces) inhibit the stacking of another holder on top of holder 15 dueto the uneven surfaces provided by the expansion of thebiopharmaceuticals held in container 10.

Outer rim 40 may include a bottom end 42 and outer rim 80 may include atop end 82, which may be connected to one another via heat sealing, orsome other means of fixedly and/or sealingly connecting the outer rimsto one another as depicted in FIGS. 1, 2 and 4. For example, flanges(not shown) may also be provided which extend outwardly from outer rims40 and 80 to allow first portion 115 and second portion 117 to bemechanically fastened to each other using fasteners, such as pop rivets,ratcheting fasteners, other fasteners, screws or bolts. Also, suchconnection may be done by welding (e.g., heat sealing, high frequencysealing or ultra sonic welding) or with adhesive. Such a connection mayinhibit contamination from passing by outer rim 40 and outer rim 80toward container 10.

The outer rims (e.g., outer rim 40 and outer rim 80) and the inner rims(e.g., inner rim 30 and inner rim 70) may include apertures such as afirst aperture 420 and a second aperture 410 depicted in FIG. 2 to allowconduits (e.g., a conduit 13) connected to container 10 to passtherethrough. Such conduits may allow filling or draining ofbiopharmaceutical materials or other solids, liquids, or gases intoand/or out of the interior (not shown) of container 10. Conduit 13 mayalso be used to insert a measurement probe (not shown) inside container10 (e.g., a pH electrode, a conductivity sensor, temperature probe, anion selective electrode, a spectophotometric probe, an ultrasoundsensor, an optic fiber.)

Conduit 13 may be integral (e.g., monolithic relative) to container 10or it may be connectable to a receiving port (not shown) thereof. Forexample, conduit 13 could be connected to a receiving port using afitting placed within the inlet port. Fittings such as those describedin U.S. Pat. No. 6,186,932, may be used for the connection of suchconduits. Also, fittings which can maintain the sterility of thecontents of the container or flexible container may preferably be used.The fittings may be configured in different shapes, such as straightfittings and/or angled fittings including ninety (90) degree elbows, ifdesired. In another example, conduit 13 may include a filter (not shown)to filter any impurities or other undesirable materials from thebiopharmaceutical material. The conduit and/or fittings may be locatedin protective cavity 45 and/or protective cavity 85, which may protectconduit 13 and the fittings from any damage resulting from impact orstress, such as the impact resulting from a person dropping holder 15when container 10 is filled with biopharmaceutical materials.

In another example depicted in FIG. 8, the outer rims (e.g., outer rim40 and outer rim 80) may also have spaces 700 (FIG. 8) that formchannels when holder 15 is connected (i.e., by interlocking teeth 450)to a second similar holder, such as a holder 415, having complementaryteeth and spaces on an outer rim thereof as depicted in FIG. 8. Spaces700 may allow heat transfer from an exterior of holder 15 to theexterior surface of a bottom 200 and a bottom 220 of the holder 15 andto the biopharmaceutical materials held in container 10 in cavity 240 ofholder 15. Any number of spaces or channels and any design or placementof the spaces or channels relative to one another may be provided tofacilitate such heat transfer. Hanging holes (not shown) may be locatedon inner rim 30 or outer rim 40 of first portion 115 and on matchinglocations on inner rim 70 or on outer rim 80 of second portion 117. Suchhanging holes allow a hanger (not shown) to be inserted therein to allowholder 15 to be suspended from such hanger. Biopharmaceutical materialsheld in container 10 may then be drained through a conduit, such asconduit 13.

In another example depicted in FIGS. 9-10, a holder 615 includes aplurality of connecting ribs 630 and a plurality of transverse ribs 635.Connecting ribs 630 connect an outer rim 640 to a cradle 602, which issimilar to that described for holder 15. Further, transverse rib 635extend transversely relative to a longitudinal dimension of a bottom 620of cradle 602 and from one side of the cradle to an opposite sidethereof. Grooves 622 are located on an opposite surface 623 of bottom620 and the grooves correspond to transverse ribs 635. The bottom may beconcave inwardly as viewed from outside cradle 602, as described abovefor holder 15 depicted in FIG. 7. Ribs 630 and transverse ribs 635provide support for cradle 602 to inhibit deformation of bottom 620 awayfrom cradle 602 in response to the freezing of biopharmaceuticalmaterials held in cradle 602. In a further example depicted in FIGS.11-12, a holder 715 includes connecting ribs 730, a transverse rib 735,and opposite curving ribs 736 which extend from opposite ends of acradle 602 toward transverse rib 735 and curve back toward the end fromwhich they started. As it is understood by one skilled in the art,support ribs may extend in various directions on a cradle, such ascradle 602 or cradle 702, to provide structural support to a cradle inresponse to biopharmaceutical materials freezing which are held in sucha cradle. As depicted in FIG. 12, grooves 722 correspond to the ribs onan opposite side of a bottom 720 such that the grooves are indentationsand the ribs are protrusions from opposite sides of bottom 720.

In another example depicted in FIGS. 13-15, a holder 815 may receivecontainer 10 and may include a first portion 820 and a second portion830 which may be connectable to a protective member 840 which maycompletely or partially surround first portion 820 and second portion830. Protective member 840 may be formed of a resilient material (e.g.,PET or HDPE) configured to absorb stresses or shocks thereon. Protectivemember 840 may be connected to first portion 820 and second portion 830via a friction fit, for example. Alternatively, ends 825 of firstportion 820 and second portion 830 may be received in a groove 847 ofmultiple portions of member 840. Such multiple portions of protectivemember 840 may then be welded or otherwise connected to one another. Asdepicted, an exterior surface 822 of first portion 820 may be recessedrelative to a top surface 845 of member 840. The recessed location ofexterior surface 822 may inhibit damage to container 10 held therein asdescribed above relative to holder 15.

Also, the holders (e.g., holder 15) may preferably be formed ofmaterials configured to support a weight of container 10 and to protectcontainer 10 from being punctured or damaged due to an impact or stresson holder 15. For example, holder 15 may be more rigid than container 10held therein. Also, the materials forming holder 15 may remain stableand retain their structural properties over a large range oftemperatures. Specifically, such materials should retain theirload-bearing capacity and exhibit cold crack temperatures no higher thannegative 80 degrees Celsius while being resistant to cleaning agents andmethods commonly used in biopharmaceutical manufacturing, e.g., sodiumhydroxide, sodium hypochloride (e.g., CLOROX), peracetic acid, etc. Forexample, first portion 115 and second portion 117 of holder 15 could beformed of injection molded plastic or thermo formed plastic, such as PET(e.g., Clear 0.05″ PET) or HDPE (e.g., 0.080″ black unfilled HDPE).Also, holder 15 may be formed of fluoropolymer resin (e.g. TEFLON),machined plastic, stainless steel or any number of other materialsincluding aluminum, polyethylene, polypropylene, polycarbonate, andpolysulfone, for example. Further materials may include compositematerials such as glass-reinforced plastic, carbon-fiber reinforcedresins, or other engineering plastic materials known to offer highstrength-to-weight rations and which are serviceable at varioustemperatures of interest. It will be understood by those skilled in theart that each of first portion 115 and second portion 117 may bemonolithic and formed as one piece or may include elements fixedlyconnected together. In addition, portions 115 and 117 may be constructedas one piece such that the portions 115, 117 may be hinged or otherwiseconnected together. Further, holder 15 could be formed of a singlematerial (e.g., injection molded plastic) or it could be formed ofdifferent materials and connected together. Also, holder 15 may beformed of a material compatible with gamma radiation.

Also, a holder (e.g., holder 15) may be formed, sized and/or dimensionedto receive and support containers of various sizes to provide additionalrigidity and support to the container(s), thus facilitating handling,storage, and/or temperature control thereof. For example, container 10may be pillow shaped and holder 15 may be elliptically shaped.

Also, it will be understood by one skilled in the art that variousholders (e.g., holder 15) may have cradles (e.g., cradle 202) configured(e.g., shaped and dimensioned) to receive various sized containers(e.g., container 10) and to be received in a temperature control unit(e.g., a blast freezer). Although the containers are described herein asflexible containers, the containers may be made of a semi-rigid materialsuch as polyethylene or the like. An example of such a container couldinclude a container similar to a standard plastic milk jug. Containersmade of such similar semi-rigid materials may benefit from additionalrigidity supplied by attachment (e.g., fixedly or releasably) to aholder, for example. Further, the containers whether formed of a rigid,flexible or semi-rigid material, contain outer surfaces which maycontact the interior surfaces of a holder which may include holes and/ormay be formed of a material to facilitate heat transfer to and from acontainer (e.g., container 10) held in such a holder (e.g., holder 15)when the holder is present in a temperature control unit, such as ablast freezer. Further, the outer surfaces of the holder receiving thecontainers for holding the biopharmaceutical materials may be in contactwith air flow in an interior (e.g., interior 500) of a blast freezer orother means of temperature control to cause the cooling and/or heatingof the container having the biopharmaceutical materials therein to causethe temperature of the biopharmaceutical materials to be controlled.

In another example, holder 15 may be formed of a foam (e.g., HDPE, EVA),or a more rigid material (e.g., foam or solid) may be utilized with sucha foam to form the holder. Also, a container, such as container 10, maybe connected to a holder, such as holder 15, by RF welding. In a furtherexample, a container and holder may be separated from one another withincradle 202 by a layer of collapsible dimples (not shown) or ribs (notshown).

The biopharmaceutical material in the containers (i.e., container 10)and holders (e.g., holder 15) described above may thus be cooled orotherwise thermoregulated (e.g., to a subzero temperature) in atemperature control unit, such as a blast freezer providing forcedconvection, for example. Alternatively, the biopharmaceutical materialsmay be frozen in a conventional laboratory freezer providing freeconvention, a plate freezer or via a liquid nitrogen path. When suchfreezing operation is completed, the containers may be removed from thetemperature control unit by removing the containers and the holders, orother support structures which the containers are received in orconnected to, for example. The holders or other support structuresholding the containers may be stored in a large chiller or freezer withan interior air temperature of about negative 20 degrees Celsius, forexample.

A typical process for processing and/or preserving a biopharmaceuticalmaterial is described as follows. One or more containers (e.g.,container 10) is received in and/or connected to a holder (e.g., holders15, 515) as depicted in FIG. 4. Also, holder 15 may be alignedsubstantially horizontally (e.g., as depicted in FIGS. 1 and 5) andbiopharmaceutical material, for example liquid biopharmaceuticalmaterial, may be inserted through conduit 13 into container 10. Also,after biopharmaceutical material is received in the interior of theholder (e.g., holders 15, 515) through a conduit (e.g., conduit 13).Holder 15 may be located in a temperature control unit, such as aninterior 500 of a blast freezer, as shown in FIG. 1. Thebiopharmaceutical contents are frozen in the temperature control tonegative 20 degrees Celsius or below, for example. After thebiopharmaceutical material in the container(s) is frozen, holder 15 andthe container(s) may be stored in the temperature control unit, such asa blast freezer, or removed therefrom and placed in a large freezer, forexample, a walk-in freezer having an interior air temperature of aboutnegative 20 degrees Celsius for storage, as is typically present inlarge medical institutions (e.g., hospitals). Also, the use ofcontainers (e.g., container 10) having a uniform thickness allow uniformcooling to occur within such a temperature control unit, blast freezer,or other means for controlling a temperature of the immediatesurroundings of such containers.

Further, the above-described containers may be removed from a freezer orother system for storage of the flexible containers and contents thereofat a controlled temperature. These containers having biopharmaceuticalmaterial therein may then be received in a temperature control unit(e.g., an interior 500 of a blast freezer) for heating, melting,agitating, mixing and/or thawing the biopharmaceutical materialcontained in the containers. For example, holder 15 supporting container10 having frozen biopharmaceutical material therein may be placed in atemperature control unit where its temperature may be controlled (e.g.thawed) by heat transfer plates or air convection (e.g., free or forcedair) heating. Also, the biopharmaceutical materials may be thawed in awater bath or in air and ambient temperature. In another example, a thinfilm heater, such as self-regulating positive temperature coefficient(PTC) heater element, may be incorporated into holder 15 to allow acontainer held therein to be thawed at a predefined setpoint using onlyan external voltage source. In addition, holder 15 may be submitted togentle mixing inside a temperature control unit to accelerate thethawing kinetics and to minimize any solute concentration gradient inthe thawed liquid.

From the above description, it will be understood to one skilled in theart that the containers described herein may be adapted for use inholders of various shapes or sizes. Further, the holders may be adaptedto receive containers of various shapes or sizes. These holders orsupport structures may be configured for long or short term storage ofthe containers containing biopharmaceutical materials in liquid orfrozen state, or may be adapted to transport the flexible containerscontaining biopharmaceutical materials in liquid or frozen state.Further, these holders and containers may be adapted for utilizationwith materials other than biopharmaceutical materials.

While the invention has been depicted and described in detail herein, itwill be apparent to those skilled in the relevant art that variousmodifications, additions, substitutions and the like can be made withoutdeparting from the spirit of the invention and these are thereforeconsidered to be within the scope of the invention as defined in thefollowing claims.

1. A system for use in freezing, storing and thawing biopharmaceuticalmaterials, said system comprising: a container for holdingbiopharmaceutical materials therein; a holder having a cavity, saidcontainer received in said cavity; said holder comprising a firstportion and a second portion, said container received between said firstportion and said second portion to connect said container to saidholder; said holder comprising an interior cradle having a bottom andedges extending from said bottom, said cradle bounding said cavity; anouter rim connected to said cradle and separated from said cavity; andwherein said bottom comprises an inner surface facing said cavityreceiving said container and an outer surface, said outer surface ofsaid bottom being recessed relative to an outer surface of said outerrim.
 2. The system of claim 1 wherein said first portion comprises afirst interior cradle portion and wherein said second portion comprisesa second interior cradle portion, said first cradle portion and saidsecond cradle portion defining said cradle bounding said cavity.
 3. Thesystem of claim 1 wherein said cradle and said container comprisesubstantially complementary shapes such that said containersubstantially conforms to an inner surface of said cradle when saidcontainer is filled with biopharmaceutical materials.
 4. The system ofclaim 1 wherein said holder comprises an inner rim having asubstantially flat inner holder portion for holding said container, saidholder portion aligned in a plane substantially parallel to said bottom.5. The system of claim 4 wherein said inner rim is configured to holdsaid container in said cradle and to allow said container to move fromoutside the cradle into the cradle in response to biopharmaceuticalmaterial being inserted into said container.
 6. The system of claim 5wherein said second portion comprises a second inner rim and said secondinner rim comprises a second substantially flat holder portionconfigured to engage said inner rim to hold said container and to allowsaid container to move from outside said cradle into said cradle inresponse to biopharmaceutical material being inserted into saidcontainer.
 7. The system of claim 1 further comprising a support ribprotruding from an outer surface of said cradle, said rib structurallysupporting said cradle to substantially maintain a shape of said cradlein response to an expansion of biopharmaceutical material held in saidcontainer due to freezing.
 8. The system of claim 7 wherein said supportrib extends from a side of said cradle to an opposite side of saidcradle.
 9. The system of claim 7 wherein said bottom comprises an innersurface facing said cavity receiving said container and opposite saidouter surface, said cradle comprising a groove in said inner surfacecorresponding to said support rib protruding from said outer surface.10. The system of claim 1 wherein said first portion comprises a firstinner rim and said second portion comprises a second inner rim, saidinner rim comprising a first plurality of teeth and said second innerrim comprising a second plurality of teeth, said first plurality ofteeth and said second plurality of teeth engageable with each other toconnect said first inner rim to said second inner rim.
 11. The system ofclaim 10 wherein said container comprises a plurality of aperturesreceiving said first plurality of teeth and said second plurality ofteeth to connect said container to said holder.
 12. The system of claim1 wherein said second portion comprises a second outer rim separatedfrom said cavity.
 13. The system of claim 12 wherein said outer rim andsaid second outer rim are sealingly connected to each other.
 14. Thesystem of claim 12 further comprising at least one conduit extendingfrom said container through at least a second cavity to an exterior ofsaid holder, said at least one conduit providing communication betweensaid container and the exterior of said holder.
 15. The system of claim12 wherein a protective cavity is bounded by said outer rim and saidsecond outer rim.
 16. The system of claim 1 wherein said outer rimcomprises a first plurality of outer teeth engageable with a secondplurality of outer teeth of a second outer rim of a second holder toinhibit movement between said holder and the second holder.
 17. Thesystem of claim 12 wherein said outer surface of said bottom is recessedtoward said cradle relative to said outer surface of said outer rim byan amount dimensioned to allow for expansion of biopharmaceuticalmaterials such that said outer surface avoids extending beyond saidouter rim.
 18. The system of claim 12 wherein said outer surface of saidbottom comprises a plurality of heat transfer apertures configured toallow heat transfer between said container and an exterior of saidcradle.
 19. A system for use in freezing, storing and thawingbiopharmaceutical materials, said system comprising: a container forholding biopharmaceutical materials therein; a holder having a cradlebounding a cavity, said container received in said cavity; said holdercomprising a first portion and a second portion forming said cradle,said container received between said first portion and said secondportion to connect said container to said holder; and a support memberprotruding from an outer surface of said cradle, said memberstructurally supporting said cradle and inhibiting deformation of saidcradle in response to an expansion of biopharmaceutical material held insaid container due to freezing.
 20. The system of claim 19 wherein saidfirst portion comprises an outer rim and said support member extendsfrom a side of said outer rim to an opposite side of said outer rim. 21.The system of claim 19 wherein said cradle comprises a bottom having aninner surface facing said cavity receiving said container and oppositesaid outer surface, said cradle comprising a groove in said innersurface corresponding to said support member protruding from said outersurface.
 22. The system of claim 20 wherein said support member connectssaid outer rim to said cradle.
 23. The system of claim 19 wherein saidsupport member extends from a first side of said cradle to a second sideof said cradle.
 24. A system for use in freezing, storing and thawingbiopharmaceutical materials, said system comprising: a container forholding biopharmaceutical materials therein; a holder having a cradlebounding a cavity, said container received in said cavity; said holdercomprising a first portion and a second portion forming said cradle,said container received between said first portion and said secondportion to connect said container to said holder; said holder comprisingan outer rim connected to said cradle; and said outer rim comprising afirst plurality of outer teeth engageable with a second plurality ofouter teeth of a second outer rim of a second holder to stack saidholder and said second holder and to inhibit movement between saidholder and said second holder.
 25. The system of claim 24 wherein saidfirst portion comprises an inner rim, said second portion comprises asecond inner rim, said inner rim comprising a first plurality of innerteeth and said second inner rim comprising a second plurality of innerteeth, said first plurality of inner teeth and said second plurality ofinner teeth engageable with each other to connect said first inner rimto said second inner rim.
 26. The system of claim 25 wherein saidcontainer comprises a plurality of apertures receiving said firstplurality of teeth and said second plurality of teeth to connect saidcontainer to said holder.
 27. The system of claim 24 wherein said secondportion comprises a second outer rim connected to said cradle, saidsecond outer rim comprising a third plurality of teeth engageable with afourth plurality of teeth of a third holder to stack said holder andsaid third holder and to inhibit movement between said holder and saidthird holder.
 28. The system of claim 27 wherein said outer rim and saidsecond outer rim are sealingly connected to each other.
 29. A method foruse in freezing, storing or thawing biopharmaceutical materials, themethod comprising: providing a holder having a cavity, the holdercomprising a first portion and a second portion, the holder comprisingan interior cradle having a bottom and edges extending from the bottom,the cradle bounding the cavity; the holder having an outer rim connectedto the cradle and separated from the cavity, and the bottom comprisingan inner surface facing the cavity and an outer surface, the outersurface of the bottom being recessed relative to an outer surface of theouter rim; and receiving a container for holding biopharmaceuticalmaterials in the cavity of the holder and between the first portion andthe second portion to connect the container to the holder.
 30. Themethod of claim 27 wherein the first portion comprises an inner rimhaving a holder portion for holding the container and the second portioncomprises a second inner rim having a second holder portion, and furthercomprising holding the container between the first inner rim and thesecond inner rim, inserting biopharmaceutical materials in the containersuch that the container moves from outside the cradle into the cradleformed by the cradle portion and a second cradle portion of the secondportion, and the container substantially conforming to an inner shape ofthe cradle.
 31. A method for use in freezing, storing and thawingbiopharmaceutical materials, the method comprising: providing a holderhaving a first portion and a second portion forming a cradle bounding acavity; receiving a container for holding biopharmaceutical materials inthe cavity of the holder and between the first portion and the secondportion to connect the container to the holder; and a support memberprotruding from an outer surface of the cradle, the support memberstructurally supporting the cradle and inhibiting deformation of thecradle in response to an expansion of biopharmaceutical materials heldin the container due to freezing.
 32. The method of claim 31 wherein thefirst portion comprises an outer rim and the support member extends froma side of the outer rim to an opposite side of the outer rim.
 33. Themethod of claim 31 wherein the cradle comprises a bottom having an innersurface facing the cavity receiving the container and opposite the outersurface, the cradle having a groove in the inner surface correspondingto the support member protruding from the outer surface.
 34. The methodof claim 31 wherein the support member connects an outer rim of thefirst portion to the cradle.
 35. The method of claim 31 wherein thesupport member extends from a first side of the cradle to a second sideof the cradle.
 36. A method for use in freezing, storing and thawingbiopharmaceutical materials, the method comprising: connecting acontainer for holding biopharmaceutical materials to a holder byreceiving the container in a cavity of a cradle of the holder, thecradle formed by a first portion and a second portion of the holder; andengaging a first plurality of outer teeth of an outer rim of the holderwith a second plurality of outer teeth of a second outer rim of a secondholder to stack the holder and the second holder and to inhibit movementbetween the holder and second holder.
 37. The method of claim 36 furthercomprising engaging a first plurality of inner teeth of an inner rim ofthe first portion with a second plurality of inner teeth of a secondinner rim of the second portion to connect the first inner rim to thesecond rim.
 38. The method of claim 36 further comprising sealing thefirst outer rim and the second rim to each other to inhibitcommunication between the cradle and an exterior of the holder.
 39. Asystem for use in freezing, storing and thawing biopharmaceuticalmaterials, said system comprising: a container for holdingbiopharmaceutical materials therein; a holder having a cavity, saidcontainer received in said cavity; said holder comprising a firstportion and a second portion, said container received between said firstportion and said second portion to connect said container to saidholder; and said holder comprising an interior cradle, said firstportion comprising a first bottom bounding said cavity and said secondportion comprising a second bottom bounding said cavity, said firstbottom and said second bottom opposite said cavity relative to eachother aid moveable apart from each other in response to thebiopharmaceutical material within said container and said cavityfreezing and expanding.
 40. The system of claim 39 wherein said firstbottom and said second bottom curve inwardly toward each other.
 41. Thesystem of claim 39 wherein the first bottom and the second bottom areconfigured to move away from each other due to the freezing such thatouter surfaces of the first bottom and the second bottom do not extendbeyond an outer rim of the holder, the outer rim connected to thecradle.
 42. A method for use in freezing, storing or thawingbiopharmaceutical materials, the method comprising: providing a holderhaving a cavity, the holder comprising a first portion and a secondportion, the holder comprising an interior cradle, the first portioncomprising a first bottom bounding the cavity and the second portioncomprising a second bottom bounding the cavity, the first bottom and thesecond bottom opposite the cavity relative to each other; receiving acontainer holding biopharmaceutical materials in the cavity of theholder and between the first portion and the second portion to connectthe container to the holder; and moving the first bottom and the secondbottom apart from each other in response to freezing and expanding thebiopharmaceutical materials within the container and the cavity.
 43. Themethod of claim 42 wherein the first bottom and the second bottom moveaway from each other due to the freezing such that the first bottom andthe second bottom are substantially parallel to each other.
 44. Themethod of claim 42 wherein the first bottom and the second bottom moveaway from each other due to the freezing such that an outer surface ofthe first bottom avoids extending beyond an outer rim of the holder, theouter rim connected to the cradle.